USPTO Patents Application 09993647

WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau

PCT

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) International Patent Classification 6
A61K 31/165, C07C 235/56

Al

(11) International Publication Number:
(43) International Publication Date:

WO 98/22103

28 May 1998 (28.05.98)

(21) International Application Number: PCT/GB97/03102

(22) International Filing Date: 12 November 1997 (12.1 1.97)

(30) Priority Data:

9623833.2

1 6 November 1 996 ( 1 6. 1 1 .96) GB

(71) Applicant (for all designated States except US): ZENECA

LIMITED [GB/GB]; 15 Stanhope Gate, London W1Y 6LN
(GB).

(72) Inventors; and

(75) Inventors/Applicants (for US only): HEDGE, Philip, John
[GB/GB]; (GB). BOYLE, Francis, Thomas [GB/GB];
Alderley Park, Macclesfield, Cheshire SK10 4TG (GB).

(74) Agent: TINSLEY, Rachel, Maria; Zeneca Pharmaceuticals, In-
tellectual Property Dept., Me reside, Alderley Park, Maccles-
field, Cheshire SK10 4TG (GB).

(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
GH, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK,
LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO,
NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR,
TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO patent (GH,
KE, LS, MW, SD, SZ, UG, ZW), Eurasian patent (AM, AZ,
BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL,
PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
ML, MR, NE, SN, TD, TG).

Published

With international search report.

(54) Title: RAF KINASE INHIBITORS

(R 1 ) t

H

CD

(CH 2 ) q

(57) Abstract

The present invention relates to pharmaceutical compositions comprising inhibitors of raf kinase of formula (I) wherein: R 1 and R 2 are
substituents on the phenyl rings; p, which may take the same or different values for R 1 and R 2 , is 0-3, and when p is 2 or 3 each group may be
the same or different; R 3 is C 1 . 4 alkyl; q is 0-4; R 4 is aryl or cycloalkyl wherein R 4 is optionally substituted with up to 3 substituents or a
pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutical^ acceptable carrier with the proviso that N-[5-(3-
cyclohexylpropionylamiiio)-2-methylphenyl]-4-hydroxybenzamide, N-[5-(3-cyclopentylpropionylamino>2-methylphenyl]-4-
acetoxybenzamide, N-[5-(3-phenylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(4-cyclohexylbutyTylamino)-2-

methylphenyl]-4-acetoxybenzamide, N-[5-(2-cyclohexylacetylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-

cyclohexylpropionylammo)-2-methylphenyl]-4-aminobenzamide, N-[5-(3-cyclohexylpropionylammo)-2-memylphenyl]-4-nitrobenzamide, N-
[5-(3-cyclohexylpropionylammo)-2-memylphenyl]-4-hyd^oxvmethylbenzamide ( N-[5-(3-cydohexylpropionylamino)-2-rnethylphenyl]-4-
methoxycarbonylbenzamide, N-[5-(3-cyclohexylpropionylarnino)-2-methylphenyl]-2-hydroxybenzamide, N-[5-(3-cyclohexylpropionylamino)-
2-methylphenyl]-3-hydroxybenzamide, N-[5-(3-cyclohexylpropionylarnino)-2-methylphenyl]benzarnide ; N-[5-(3-cyclohexylpropionylamino)-
2-methylphenyl]-4-acetoxybenzamide and N-[5-(3-cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxybenzamide are excluded. Processes
for their preparation and their use as therapeutic agents. A particular use is in cancer therapy.

FOR THE PURPOSES OF INFORMATION ONLY

Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.

AL

Albania

ES

Spain

LS

Lesotho

SI

Slovenia

AM

Armenia

FI

Finland

LT

Lithuania

SK

Slovakia

AT

Austria

FR

France

LU

Luxembourg

SN

Senegal

AU

Australia

GA

Gabon

LV

Latvia

SZ

Swaziland

AZ

Azerbaijan

GB

United Kingdom

MC

Monaco

TD

Chad

BA

Bosnia and Herzegovina

GE

Georgia

MD

Republic of Moldova

TG

Togo

BB

Barbados

GH

Ghana

MG

Madagascar

TJ

Tajikistan

BE

Belgium

GN

Guinea

MK

The former Yugoslav

TM

Turkmenistan

BF

Burkina Faso

GR

Greece

Republic of Macedonia

TR

Turkey

BG

Bulgaria

HU

Hungary

ML

Mali

TT

Trinidad and Tobago

BJ

Benin

IE

Ireland

MN

Mongolia

UA

Ukraine

BR

Brazil

IL

Israel

MR

Mauritania

UG

Uganda

BY

Belarus

IS

Iceland

MW

Malawi

US

United States of America

CA

Canada

IT

Italy

MX

Mexico

uz

Uzbekistan

CF

Central African Republic

JP

Japan

NE

Niger

VN

Viet Nam

CG

Congo

KE

Kenya

NL

Netherlands

YU

Yugoslavia

CH

Switzerland

KG

Kyrgyzstan

NO

Norway

zw

Zimbabwe

CI

cate d'lvoire

KP

Democratic People's

NZ

New Zealand

CM

Cameroon

Republic of Korea

PL

Poland

CN

China

KR

Republic of Korea

PT

Portugal

cu

Cuba

KZ

Kazakstan

RO

Romania

cz

Czech Republic

LC

Saint Lucia

RU

Russian Federation

DE

Germany

LI

Liechtenstein

SD

Sudan

DK

Denmark

LK

Sri Lanka

SE

Sweden

EE

Estonia

LR

Liberia

SG

Singapore

WO 98/22103

- 1 -

PCT/GB97/03102

RAF KINASE INHIBITORS

This invention relates to compounds that inhibit the enzyme raf kinase (raf), an
enzyme which acts downstream of ras and plays a crucial role in transduction of signal
5 towards the nucleus. The invention also relates to methods of manufacturing the compounds,
pharmaceutical compositions and methods of treating diseases, especially cancer, which are
mediated through raf kinase activity.

Oncogenic forms of ras are found in 30% of all cancers, including colon (50%), lung
(30%) and pancreas (90%). Mutated, oncogenic forms of the ras GTP-binding proteins are

1 0 insensitive to activation of their intrinsic GTPase activity and therefore locked in an active
form, constitutively activating downstream components of a mitogenic signalling pathway.
Several groups simultaneously demonstrated that ras binds directly to the product of the raf
proto-oncogene, c-raf-1, thus implicating raf as an effector of ras mediated signalling (Cell
(1993) 74, 308-3 13). Raf lies at the top of a kinase cascade which results in activation of

1 5 MEK (Map kinase kinase) and then MAP-kinase and subsequent transcriptional activation of
genes involved in cell proliferation. This, coupled with previous evidence that raf is an
essential downstream component of ras signalling and is itself oncogenically transforming
when in a constitutively active form, highlights raf as a critical effector of ras mediated
transformation.

20 Evidence that inhibition of raf will result in anti-tumour activity is set out in the

following references.

1) Dominant-negative ras mutants block ras function and raf-1 activation by serum or
TP A in NIH3T3 cells (Oncogene (1992) 7, 1867-1873).

2) Genetic evidence in Drosophila and C. elegans shows that raf is essential for ras
25 stimulated differentiation (Nature (1993) 360, p600-603; Nature (1993) 363,

133-139).

3) Constitutively active mutants of MEK (the downstream target of raf) have been shown
to transform NIH3T3 cells (Science (1994) 265, 966-970). Moreover, dominant negative
mutants of MEK have been shown to reverse the tumourigenicity of ras transformed cell lines

30 (Cell (1994) 77, 841-852).

WO 98/22103 PCT/GB97/03102

-2-

4) PD098059, a selective inhibitor of MEK activation by raf and other MEK activators
(J. Biol. Chem. (1995) 270, 27489-27494) has been shown to block the MAP kinase pathway
and reverse the transformation of at least some ras transformed cell lines (Proc. Natl. Acad.
Sci. USA (1995) 92, 7686-7689).
5 5) Inhibition of raf function (through use of dominant negative raf or antisense to raf)
blocks ras-induced growth or ras-induced reporter gene expression (Nature (1991) 349, 416-
428; Genes & Dev. (1992) 6, 545-556).

6) Ras antisense has antitumour activity in human tumour mouse xenograft models
(Nature Medicine (1996), 2, 668-675).
10 Taken together, these findings indicate that raf is both a direct and major effector of

ras function and as such inhibition of the kinase activity of raf is expected to have antitumour
activity in at least a proportion of human tumours.
Specific cancers of interest include:

-carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary,
1 5 pancreas, stomach, cervix, thyroid and skin;

-hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia,
B-cell lymphoma and Burketts lymphoma;

- hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous
leukemias and promyelocytic leukemia;

20 -tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and

- other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and

glioma.

Raf inhibitors may also be useful in the treatment of diseases other than cancer that
may be associated with signal transduction pathways operating through Ras, e.g.,
25 neuro-fibromatosis.

According to one aspect of the present invention there is provided a pharmaceutical
composition comprising an inhibitor of raf kinase of the formula I

WO 98/22103

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PCT/GB97/03102

R 4

wherein:

R' and R 2 , which may be the same or different are selected from
hydroxy, C,. 6 alkoxy, mercapto, C,_ 6 alkylthio, amino, C,. 6 alkylamino,
5 di-(C,. 6 alkyl)amino, carboxy, C,_ 6 alkoxycarbonyl, carbamoyl, C,_ 6 alkylcarbamoyl,
di-C,. 6 alkylcarbamoyl, C,_ 6 alkylsulphonyl, arylsulphonyl, C,. 6 alkylaminosulphonyl,
di-(C,. 6 alkyl)aminosulphonyl, nitro, cyano, cyanoC,_ 6 alkyl, hydroxyC,. 6 alkyl, aminoC,. 6 alkyl,
C,. 6 alkanoylamino, C|. f) alkoxycarbonylamino, C,. 6 alkanoyl, C,. 6 alkanoyloxy, C,. 6 alkyl, halo,
trifluoromethyl, aryl, arylC,. 6 alkyl, arylC,_ 6 alkoxy, heteroaryl, heteroarylC,. 6 alkyl,
10 heterocyclyl and heterocyclylC,. 6 alkyl;

p, which may take the same or different values for R 1 and R 2 , is 0-3, and when p is 2 or 3 each
group may be the same or different;
R 3 is C M alkyl;
q is 0-4;

15 R 4 is aryl or cycloalkyl wherein R 4 is optionally substituted with upto 3 substituents having
any value defined for R 1 ;

or a pharmaceutical ly-acceptable salt or in vivo hydrolysable ester thereof and a
pharmaceutically-acceptable carrier with the proviso that N-[5-(3-cyclohexyl-
propionylamino)-2-methy lpheny 1 ]-4-hydroxy benzamide, N- [5 -(3 -

20 cyclopentylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
phenylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(4-
cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(2-
cyclohexylacetylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-aminobenzamide, _N-[5-(3-

25 cyclohexylpropionylamino)-2-methylphenyl]-4-nitrobenzamide, N-[5-(3-

cyclohexylpropionylamino)-2-methylphcnyl]-4-hydroxymethylbenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-methoxycarbonylbenzamide, N-[5-(3-

WO 98/22103 PCT/GB97/03102

-4-

cyclohexylpropionylamino)-2-methylphenyl]-2-hydroxybenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-3-hydroxybenzamide,
N-[5-(3-cyclohexylpropionylamino)-2-methylphenyl]benzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
5 cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxybenzamide,
are excluded.

The first excluded compound is known as RPR 102359 and is described as
upregulating LDL receptors by Brown et al in Atherosclerosis (1994) 109:1 13-1 14. The other
excluded compounds are also described as upregulating LDL receptors by Brown et al in J.

10 Med. Chem. (1996), 39(17): 3343-3356.

Other compounds within the scope of Formula I are known outside the pharmaceutical
field from: Japanese patent 62198852, Nozue et al, Japan Synthetic Rubber Company,
Positive-type radiation resist composition; US patent 4410681, Prindle, Dow Chemical
Company, Epoxy resins cured with salicyloyl hydrocarbylamines; US patent 4367328,

15 Bertram et al, Dow Chemical Company, Epoxy resins from hydroxybenzamides; Japanese
patent JP 53079835, Tanaka et al, Hitachi Limited, Dialkylaminoethyl trimellitate epoxy
resin hardeners; German patent DE 2552609, Salle et al, Institut Francais du Petrole,
Aromatic diester diamides; Japanese patent JP 50105558, Kubota et al, Adeka Argus
Chemical Company, Polymers, hydrocarbon oils and rubbers resistant to metal induced

20 degradation; Japanese patent JP 61204221, Nishizawa et al, Hitachi Chemical Company,
Compatible thermosetting epoxy resin compositions; Netherlands patent application 651441 1,
J R Geigy, Heterocyclic aromatic pigments; and Chem Abs CA 64, 19459g, Tallec et al,
Selective reduction of some alkyl-substituted dinitrobenzenes at controlled potential. The
reader is directed to these references for general guidance on synthesis of compounds within

25 the scope of Formula I.

"Aryl" in the terms "aryl", "arylC,. 6 alkyl" and "arylCi_ 6 alkoxy" typically means
phenyl or naphthyl, preferably phenyl. "Heteroaryl" in the terms "heteroaryl" and
"heteroarylC,. 6 alkyl" means an aromatic mono- or bicyclic 5-10 membered ring with up to
five ring heteroatoms selected from nitrogen, oxygen and sulphur. Examples of 'heteroaryl'

30 include thienyl, pyrrolyl, furyl, imidazolyl, thiazolyl, pyrimidinyl, pyridyl, indolyl,
benzimidazolyl, benzothiazolyl, quinolyl and isoquinolyl. "Heterocyclyl" in the terms

WO 98/22103

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PCT/GB97/03102

"heterocyclyl" and "heterocyclic, _ 6 alkyr means a non-aromatic mono- or bicyclic 5-10
membered ring with up to five ring hetero atoms selected from nitrogen, oxygen and sulphur.
Examples of 'heterocyclyl' include pyrrolidinyl, morpholinyl, piperidinyl, dihydropyridinyl
and dihydropyrimidinyl. "Cycloalkyl" means a non-aromatic mono- or bicyclic 5-10
5 membered carbon ring. Examples of "cycloalkyl" include cyclopentyl, cyclohexyl,
cycloheptyl, bicyclo[2.2.1]heptyl and bicyclo[4.4.0]decyl.

Typical values for generic groups include: C,. 6 aIkoxy for example methoxy,
C,. 6 aIkylthio for example methylthio, C^alkylamino for example methylamino,
di-(C 16 alkyl)amino for example dimethylamino, Ci_ 6 alkoxycarbonyl for example
10 methoxycarbonyl or ethoxycarbonyl, C,. 6 aIkylcarbamoyl for example methylcarbamoyl, di-
C,. 6 alkylcarbamoyl for example dimethylcarbamoyl,

C^ 6 aIkylsulphonyl for example methylsulphonyl, arylsulphonyl for example
phenylsulphonyl, C,. 6 alkyIaminosulphonyl for example methylaminosulphonyl,
di-(C,. 6 alkyl)aminosulphonyI for example dimethylaminosulphonyl, cyanoC,. 6 alkyl for

15 example cyanomethyl, hydroxyC 16 alkyl for example hydroxymethyl, aminoC 16 alkyl for
example aminoethyl, C,. 6 alkanoylamino for example formamido and acetamido, C,_
6 alkoxycarbonylamino for example methoxycarbonylamino, Ci_ 6 alkanoyl for example
formyl and acetyl, C, 6 aIkanoyloxy for example acetoxy, C 16 alkyl for example methyl, ethyl,
isopropyl or tert-butyl, halo for example fluoro, chloro or bromo, aryl for example phenyl,

20 ary!C,. 6 alkyl for example benzyl, aryloxy for example phenoxy and arylC 1(i aIkoxy for
example benzyloxy.

Any ring in R 1 or R 2 may be optionally substituted, for example by upto 3
substituents. Suitable substituents include hydrogen, hydroxy, C,_ 6 alkoxy, mercapto,
C,. 6 alkylthio, amino, C,. 6 alkylamino, di-(C,. 6 alkyl)amino, carboxy, carbamoyl,

25 C,. 6 alkylcarbamoyl, di-C,. 6 alkylcarbamoyl, C,. 6 alkylsulphonyl, arylsulphonyl,

C,. 6 alkylaminosulphonyl, di-(C,. f ,alkyl)aminosulphonyl, nitro, cyano, cyanoC,. 6 alkyl,
hydroxy C,. 6 alkyl, aminoC,. 6 alkyl, C,. 6 alkanoylamino, C,. 6 alkoxycarbonylamino,
C,. 6 alkanoyl, C,. 6 alkanoyloxy, C,. 6 alkyl, halo and trifluoromethyl.

In this specification the generic term "alkyl" includes both straight-chain and

30 branched-chain alkyl groups. However references to individual alkyl groups such as "propyl"
are specific for the straight-chain version only and references to individual branched-chain

WO 98/22103 PCT7GB97/03102

- 6 -

alkyl groups such as "isopropyl" are specific for the branched-chain version only. An
analogous convention applies to other generic terms.

It is to be understood that, insofar as certain of the compounds of Formula I defined
above may exist in optically active or racemic forms by virtue of one or more asymmetric
5 carbon atoms, the invention includes in its definition any such optically active or racemic
form which possesses the property of inhibiting raf. The synthesis of optically active forms
may be carried out by standard techniques of organic chemistry well known in the art, for
example by synthesis from optically active starting materials or by resolution of a racemic
form. Similarly, inhibitory properties against raf may be evaluated using the standard

1 0 laboratory techniques referred to hereinafter.

Particular values for R 1 include hydroxy; hydroxyC,. 6 alkyl for example hydroxymethyl
and hydroxyethyl; carboxy; carbamoyl; C,. 6 alkylcarbamoyl for example mefhylcarbamoyl and
ethylcarbamoyl; di-C,. 6 alkylcarbamoyl for example di-methylcarbamoyl, di-ethylcarbamoyl
and N-ethyl-N-methylcarbamoyl; nitro; cyano;

15 C,. 6 alkoxy for example methoxy, ethoxy, propoxy and isopropoxy; amino; C,. 6 alkylamino for
example methylamino, ethylamino and propylamino; di-(C,_ 6 alkyl)amino for example
di-methylamino, di-ethylamino and N-ethyl-N-methylamino; and C,. 6 alkoxycarbonyl for
example methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.

Preferred values for R 1 are hydroxy, amino, C,. 6 alkylamino, di-(C,. 6 alkyl)amino,

20 C,. 6 alkoxy and C,_ 6 alkoxycarbonyl; more preferably hydroxy, methylamino, ethylamino,
propylamino, di-methylamino, di-ethylamino and N-ethyl-N-methylamino. Preferred
positions for substitution of R 1 into the phenyl ring indicated in Formula I are 3, 4 and/or 5;
more preferably 3; 4; 3,4 or 3,5. Favourably R 1 is selected from 4-hydroxy; 4-dimethylamino;
3-methoxy; 3,5-dimethoxy; 3-methoxycarbonyl; and 4-hydroxy-3 -methoxy: of these

25 4-hydroxy is most preferred.

R 2 is preferably hydrogen.

Preferred values for p in (R') p are 1-2, especially 1.
A preferred value for p in (R 2 ) p is 0.

Particular values for q are 0-3, 0-2 or 0-1 . A preferred value for q is 0.
30 R 3 is preferably C,_,alkyl, more preferably methyl or ethyl and especially methyl.

R 4 is preferably aryl, more preferably phenyl, more preferably monosubstituted phenyl

WO 98/22103

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PCT/GB97/03102

and especially monosubstituted phenyl in the meta position, preferably with an electron
withdrawing substituent group. Typical electron withdrawing groups include amino,
C,. 6 alkylamino, di-(C,_ 6 alkyl)amino, carboxy, C,. 6 alkylsulphonyl, arylsulphonyl, nitro, cyano,
halo, and trifluoromethyl; of these amino, C,. 6 alkylamino, di-(C,. 6 alkyl)amino, nitro, cyano
5 and halo are preferred; more preferably di-(C,. 6 alkyl)amino; more preferably

di-(C l . 4 alkyl)amino; and especially any of di-methylamino, di-ethylamino and N-ethyl-N-
methylamino.

Particular combinations of R 1 and (CH 2 ) q -R 4 include:
R ' (CH 2 ) ( ,-R 4
4-hydroxy 3-dimethylaminophenyl
4-hydroxy cyclohexylethyl
4-hydroxy 3 ,4-dichlorophenylmethyl

4-hydroxy bicyclo[2.2. 1 ]hept-2-ylmethyl

4-dimethy lamino 3 -dimethy laminopheny 1

3- methoxy 3-dimethylaminophenyl
3,5-dimethoxy 3-dimethylaminophenyl
3 -methoxycarbonyl 3 -dimethylaminopheny 1

4- hydroxy-3-methoxy 3-dimethylaminophenyl

10 and with respect to these combinations, R 2 is preferably hydrogen and R 3 is preferably
methyl.

According to another aspect of the present invention there is provided an inhibitor of
raf kinase of formula II:

R 3

-(R 2 ) P

(R 1 ) f

Formula II \-( \

P ,R 5

n-4

(CH 2 )

q

15 wherein:

R 1 and R 2 , which may be the same or different are selected from

WO 98/22103

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PCT/GB97/03102

hydroxy, C,_ 6 alkoxy, mercapto, C,. 6 alkylthio, amino, C,. 6 alkylamino,
di-(C,. 6 alkyl)amino. carboxy, C,_ 6 alkoxycarbonyl, carbamoyl, C,. 6 alkylcarbamoyl,
di-C,. 6 alkylcarbamoyl, C,. 6 alkylsulphonyl, arylsulphonyl, C,. 6 alkylaminosulphonyl,
di-(C,. 6 alkyl)aminosulphonyl, nitro, cyano, cyanoC,. 6 alkyl, hydroxyC,. 6 alkyl, amino Chalky 1,
5 C,. 6 alkanoylamino, C,. 6 alkoxycarbonylamino, C,. 5 alkanoyl, C,. 6 alkanoyloxy, C,_ 6 alkyl, halo,
trifluoromethyl, aryl, arylC,. 6 alkyl, arylC,_ 6 alkoxy, heteroaryl, heteroarylC,. 6 alkyl,
heterocyclyl and heterocyclylC,. 6 alkyl;

p, which may take the same or different values for R 1 and R 2 , is 0-3, and when p is 2 or 3 each
group may be the same or different;
10 R 3 is C,_ 4 alkyl;
q is 0-4;

R s is selected from hydroxy, C,. 6 alkoxy, mercapto, C,. 6 alkylthio, amino, C,. 6 alkylamino,
di-(C,. 6 alkyl)amino, carboxy, C,. 5 alkoxycarbonyl, carbamoyl, C,. 6 alkylcarbamoyl,
di-C,. 6 alkylcarbamoyl, C,. 6 alkylsulphonyl, arylsulphonyl, C,. 6 alkylaminosulphonyl,
15 di-(C,. 6 alkyI)aminosulphonyl, nitro, cyano, cyanoC,. 6 alkyl, hydroxyC,. 6 alkyl, aminoC,. 6 alkyl,
C,. 6 aIkanoylamino, C,_ 6 alkoxycarbonylamino, C,. 6 aIkanoyl, C,_ 6 alkanoyloxy, halo, and
trifluoromethyl,

or a pharmaceutical^ acceptable salt or in vivo hydrolysable ester thereof with the proviso

that methyl 3-[5-(3-methoxycarbonylbenzamido)-2-methylphenyl]aminocarbonylbenzoate is
20 excluded.

In another aspect a preferred individual compound of the invention is N-{5-[2-(3- N,N -
dimethylaminophenyl)acetylamino]-2-methylphenyl}-4-hydroxybenzamide
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.

Typical and preferred values for (R') p , (R 2 ) p , R 3 and q in Formula II are as set herein in

25 relation to Formula I. R 5 is preferably an electron withdrawing group. Typical electron
withdrawing groups include amino, C,. 6 alkylamino, di-(C,_ 6 alkyl)amino, carboxy,
C,. 6 alkylsulphonyl, arylsulphonyl, nitro, cyano, halo, and trifluoromethyl; of these amino,
C,. 6 alkylamino, di-(C,. 6 alkyl)amino, nitro, cyano and halo are preferred; more preferably
di-(C,. 6 alkyl)amino; more preferably di-(C M alkyl)amino; and especially any of

30 di-methylamino, di-ethylamino and N-ethyl-N-methylamino.

WO 98/22103 PCT/GB97/03102

-9 -

The excluded compound is known from German patent DE 2552609, Salle et al,
Institut Francais du Petrole, Aromatic diester diamides.

Various forms of prodrugs are known in the art. For examples of such prodrug
derivatives, see:

5 a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and
H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard
p. 113-191 (1991);

10 c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard. et al, Journal of Pharmaceutical Sciences, 77, 285 (1988); and

e) N. Kakeya, et al, Chem Pharm Bull, 32, 692 (1984).

M vivo hydrolysable esters are those pharmaceutical^ acceptable esters that hydrolyse

in the human body to produce the parent compound. Such esters can be identified by
1 5 administering, for example intravenously to a test animal, the compound under test and

subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for

carboxy include methoxymethyl and for hydroxy include acetyl.

Examples of pro-drugs include in vivo hydrolysable esters of a compound of the

Formula I. An in vivo hydrolysable ester of a compound of the Formula I containing a
20 carboxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the

human or animal body to produce the parent acid. Suitable pharmaceutically-acceptable

esters for carboxy include C,. 6 alkoxymethyl esters for example methoxymethyl, C,.

6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 _

8 cycloalkoxycarbonyloxyC,. 6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-
25 dioxolan-2-ylmethyl esters for example 5-methyl-l ,3-dioxolan-2-ylmethyl; and C,_

6 alkoxycarbonyloxyethyl esters for example 1 -methoxycarbonyloxyethyl and may be formed

at any carboxy group in the compounds of this invention.

When the compound contains a basic moiety it may form pharmaceutically

acceptable salts with a variety of inorganic or organic acids, for example hydrochloric,
30 hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. A suitable

pharmaceutically-acceptable salt of the invention when the compound contains an acidic

WO 98/22103 PCT/GB97/03102

- 10 -

moiety is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal
salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic
base which affords a pharmaceutically-acceptable cation, for example a salt with
methylamine, dimethylamine, trimethylamine, piperidine, morpholine or
5 tris-(2-hydroxyethyl)amine.

In order to use a compound of the Formula I or a pharmaceutically acceptable salt or
in vivo hydrolysable ester thereof for the therapeutic treatment (including prophylactic
treatment) of mammals including humans, it is normally formulated in accordance with
standard pharmaceutical practice as a pharmaceutical composition.

1 0 The compositions of the invention may be in a form suitable for oral use (for example

as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible
powders or granules, syrups or elixirs), for topical use (for example as creams, ointments,
gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for
example as a finely divided powder or a liquid aerosol), for administration by insufflation (for

1 5 example as a finely divided powder) or for parenteral administration (for example as a sterile
aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing
or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using
conventional pharmaceutical excipients, well known in the art. Thus, compositions intended

20 for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or
preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for
example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium
carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding

25 agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc;
preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as
ascorbic acid. Tablet formulations may be uncoated or coated either to modify their
disintegration and the subsequent absorption of the active ingredient within the
gastrointestinal tract, or to improve their stability and/or appearance, in either case, using

30 conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the

WO 98/22103 PCT/GB97/03102

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active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with
water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form
5 together with one or more suspending agents, such as sodium carboxymethylcellulose,

methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum
tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation
products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or
condensation products of ethylene oxide with long chain aliphatic alcohols, for example

10 heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters
derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters
derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or

1 5 condensation products of ethylene oxide with partial esters derived from fatty acids and

hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions
may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-
oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening
agents (such as sucrose, saccharine or aspartame).

20 Oily suspensions may be formulated by suspending the active ingredient in a vegetable

oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid
paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard
paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring
agents may be added to provide a palatable oral preparation. These compositions may be

25 preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by
the addition of water generally contain the active ingredient together with a dispersing or
wetting agent, suspending agent and one or more preservatives. Suitable dispersing or
wetting agents and suspending agents are exemplified by those already mentioned above.

30 Additional excipients such as sweetening, flavouring and colouring agents, may also be
present.

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The pharmaceutical compositions of the invention may also be in the form of
oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil,
or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable
emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum
5 tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial
esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and
condensation products of the said partial esters with ethylene oxide such as polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening, flavouring and
preservative agents.

10 Syrups and elixirs may be formulated with sweetening agents such as glycerol,

propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent,
preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterile injectable
aqueous or oily suspension, which may be formulated according to known procedures using
15 one or more of the appropriate dispersing or wetting agents and suspending agents, which
have been mentioned above. A sterile injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a
solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredient with a
20 suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal
temperature and will therefore melt in the rectum to release the drug. Suitable excipients
include, for example, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or
suspensions, may generally be obtained by formulating an active ingredient with a
25 conventional, topically acceptable, vehicle or diluent using conventional procedures well
known in the art.

Compositions for administration by insufflation may be in the form of a finely divided
powder containing particles of average diameter of, for example, 30p.m or much less, the
powder itself comprising either active ingredient alone or diluted with one or more
30 physiologically acceptable carriers such as lactose. The powder for insufflation is then

conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for

WO 98/22103 PCT/GB97/03102

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use with a turbo-inhaler device, such as is used for insufflation of the known agent sodium
cromo glycate.

Compositions for administration by inhalation may be in the form of a conventional
pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing
5 finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile
fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently
arranged to dispense a metered quantity of active ingredient.

For further information on Formulation the reader is referred to Chapter 25.2 in
Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial
10 Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or more excipients to
produce a single dosage form will necessarily vary depending upon the host treated and the
particular route of administration. For example, a formulation intended for oral
administration to humans will generally contain, for example, from 0.5 mg to 2 g of active
1 5 agent compounded with an appropriate and convenient amount of excipients which may vary
from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will
generally contain about 1 mg to about 500 mg of an active ingredient. For further information
on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in
Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial
20 Board), Pergamon Press 1 990.

The size of the dose for therapeutic or prophylactic purposes of a compound of the
Formula I will naturally vary according to the nature and severity of the conditions, the age
and sex of the animal or patient and the route of administration, according to well known
principles of medicine. As mentioned above, compounds of the Formula I are useful in
25 treating diseases or medical conditions which are due alone or in part to the effects of raf
kinase activity.

In using a compound of the Formula I for therapeutic or prophylactic purposes it will
generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per
kg body weight is received, given if required in divided doses. In general lower doses will be
30 administered when a parenteral route is employed. Thus, for example, for intravenous
administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will

WO 98/22103 PCT/GB97/03102

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generally be used. Similarly, for administration by inhalation, a dose in the range, for
example, 0.5 mg to 25 mg per kg body weight will be used. Oral administration is however
preferred, particularly in tablet form. Typically, unit dosage forms will contain about 1 mg to
500 mg of a compound of this invention.
5 Compounds of this invention may be useful in combination with known anti-cancer

and cytotoxic agents. If formulated as a fixed dose such combination products employ the
compounds of this invention within the dosage range described herein and the other
pharmaceutically active agent within its approved dosage range. Sequential use is
contemplated when a combination formulation is inappropriate.
10 Therefore in a further aspect, the present invention provides a compound of the

Formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in
a method of therapeutic treatment of the human or animal body.

In yet a further aspect, the present invention provides a compound of the Formula I or N-[5-
(3 -cyclohexy Ipropiony lamino)-2-methy lpheny 1] -4-hy droxybenzamide , N-[5-(3-

1 5 cyclopentylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
pheny Ipropiony lamino)-2 -methy lpheny 1] -4-acetoxybenzamide, N- [5 -(4-
cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(2-
cyclohexylacetylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-aminobenzamide, _N-[5-(3-

20 cyclohexylpropionylamino)-2-methylphenyl]-4-nitrobenzamide, N-[5-(3-

cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxymethylbenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-methoxycarbonylbenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-2-hydroxybenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-3-hydroxybenzamide,

25 N-[5-(3-cyclohexylpropionylamino)-2-methylphenyl]benzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxybenzamide, (hereinafter excluded
compounds) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use
in treating a disease condition mediated by raf kinase.

30 In yet a further aspect the present invention provides a method of treating a disease or

medical condition mediated by raf kinase which comprises administering to a warm-blooded

WO 98/22103 PCT/GB97/03102

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animal an effective amount of a compound of the Formula I or excluded compound or a
pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.

The present invention also provides the use of a compound of the Formula I or
excluded compound or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof
5 in the preparation of a medicament for use in a disease condition mediated by raf kinase.

Although the compounds of the Formula I are primarily of value as therapeutic agents
for use in warm-blooded animals (including man), they are also useful whenever it is required
to inhibit the effects of raf kinase. Thus, they are useful as pharmacological standards for use
in the development of new biological tests and in the search for new pharmacological agents.
1 0 The compounds of Formula I are especially useful in treatment of tumours having a

high incidence of ras mutation, such as colon, lung, and pancreatic tumours. By the
administration of a composition having one (or a combination) of the compounds of this
invention, development of tumours in a mammalian host is reduced.

In yet a further aspect, the present invention provides a compound of the Formula I or
1 5 excluded compound or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof
in the preparation of a medicament for treating cancer.

In another aspect the present invention provides a process for preparing a compound of
the Formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof which
process comprises:
20 reacting a compound of the Formula III:

N-H

Formula III \-(

with a compound of the Formula IV

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PCT/GB97/03102

o

(CH 2 ) q R 4

Formula IV

or an activated derivative thereof, under standard amide bond forming conditions, wherein
variable groups are as hereinbefore defined wherein any functional group is protected, if
necessary, and:
5 i. removing any protecting groups;

ii. optionally forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.

Typically a carbodiimide coupling reagent is used in the presence of an organic
solvent (preferably an anhydrous polar aprotic organic solvent) at a non-extreme temperature,
for example in the region -10 to 40°, typically ambient temperature of about 20°C.
10 Protecting groups may in general be chosen from any of the groups described in

the literature or known to the skilled chemist as appropriate for the protection of the group in
question, and may be introduced by conventional methods.

Protecting groups may be removed by any convenient method as described in the
literature or known to the skilled chemist as appropriate for the removal of the protecting
15 group in question, such methods being chosen so as to effect removal of the protecting group
with minimum disturbance of groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake of
convenience, in which "lower" as in, for example, lower alkyl signifies that the group to
which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples
20 are not exhaustive. Where specific examples of methods for the removal of protecting groups
are given below these are similarly not exhaustive. The use of protecting groups and methods
of deprotection not specifically mentioned is of course within the scope of the invention.

A carboxy protecting group may be the residue of an ester-forming aliphatic or
araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably
25 containing 1-20 carbon atoms).

Examples of carboxy protecting groups include straight or branched chain
Ci_i 2 alkyl groups (for example isopropyl, t-butyl); lower alkoxy lower alkyl groups (for
example methoxy methyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower

WO 98/22103

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PCT/GB97/03102

alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl,
pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (for example
1 -methoxycarbonyloxy ethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (for
example benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl);
tri(lower alkyl)silyl groups (for example trimethylsilyl and t-butyldimethylsilyl); tri(lower
alkyl)silyl lower alkyl groups (for example trimethylsilylethyl); and C 2 - 6 alkenyl groups (for
example allyl and vinylethyl).

Methods particularly appropriate for the removal of carboxy protecting groups
include for example acid-, base-, metal- or enzymically-catalysed hydrolysis.

Examples of hydroxy protecting groups include lower alkyl groups
(for example t-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for
example acetyl); lower alkoxycarbonyl groups (for example t-butoxycarbonyl); lower
alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups
(for example benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,
p-nitrobenzyloxycarbonyl);

tri lower alkylsilyl (for example trimethylsilyl, t-butyldimethylsilyl) and aryl lower alkyl (for
example benzyl) groups.

Examples of amino protecting groups include formyl, aralkyl groups (for
example benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and
2,4-dimethoxybenzyl. and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower
alkanoyl (for example acetyl); lower alkoxycarbonyl (for example t-butoxycarbonyl); lower
alkenyloxycarbonyl (for example allyloxycarbonyl); aryl lower alkoxycarbonyl groups (for
example benzyloxycarbonyl, r>methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,
p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl and t-butyldimethylsilyl);
alkylidene (for example methylidene); benzylidene and substituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groups include, for
example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as
P-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for
groups such as o-nitrobenzyloxycarbonyl.

The reader is referred to Advanced Organic Chemistry, 4th Edition, by Jerry March,
published by John Wiley & Sons 1992, for general guidance on reaction conditions and

WO 98/22103 PCT/GB97/03102

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reagents. The reader is referred to Protective Groups in Organic Synthesis, 2nd Edition, by
Green et al. , published by John Wiley & Sons for general guidance on protecting groups.

The compound of Formula III may be prepared by reduction of the corresponding nitro
compound of Formula V.

5 Formula V

Typical reaction conditions include the use of ammonium formate in the presence of a
catalyst (for example palladium on carbon) in the presence of an organic solvent (preferably a
polar protic solvent), preferably with heating, for example to about 60°. Any functional
groups are protected and deprotected as necessary.
0 The compound of Formula V may be prepared by reaction of a compound of Formula

VI with a compound of Formula VII under suitable amide bond forming conditions.

\=y o-h

Formula VI

15

Formula VII

Typical conditions include activating the carboxyl group of the compound of Formula
VI for example by treatment with a halo reagent (for example oxalyl chloride) to form an acyl

WO 98/22103 PCT/GB97/03102

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halide in an organic solvent at ambient temperature, then reacting the activated compound
with the compound of Formula VII. Any functional groups are protected and deprotected as
necessary.

The following biological assays, data and Examples serve to illustrate the present
5 invention.

Biological Assays

Standard methods for assaying raf activity are described by Alessi et al. in Methods in
Enzymology Volume 255, 279-290. Particular methods are outlined below.

a) Method for assaying raf activity by means of phosphorylation of MEK

1 0 Add 2 units active raf enzyme to 2.7ug of Glutathione S-transferase MAP/ERK

Kinase (GST-MEK), prepared from E. coli by standard procedures, in 30ul of 50mM Tris-
HC1 pH7.4, 0.1 mM Ethylene Glycol bis (P -Aminoethylether)NNNN-Tetra-acetic Acid
(EGTA), lmg/ml Bovine Serum Albumin (BSA), ImM sodium vanadate, 0.03% Brij-35,
0.1% p-mercaptoethanol. Add lOul of inhibitor in 0.1% DMSO. Add lOul of Mg Adenosine

15 Triphosphate (ATP) mix (50mM Mg Acetate, 50uM ATP,lu€i y 33 P ATP. Incubate at room
temperature for 90 minutes, stop reaction by adding 20ul SDS sample buffer and load on
Sodium Dodecyl Sulfate (SDS) polyacrylamide gel. Fix the gel, dry and expose to X-ray film
or a phosphorimager screen overnight. Phosphorimager analysis allows quantification of the
raf activity by measurement of the intensity of the signal from the 70KD GST-MEK band,

20 thus allowing measurement of compound potency against raf.

b) Method for assaying raf activity by means of activating MEK
Method 1

Mix 0.1 units of raf to 0.5ug GST-MEK, 1.1 ug Glutathione S-Transferase Mitogen
Activated Protein Kinase (GST-MAP kinase) and 17jag myelin basic protein in 30ul final

25 volume of 50mM Tris-HCl pH7.4, O.lmM EGTA, lmg/ml BSA, ImM sodium vanadate,

0.03% Brij-35, 0.1% P-mercaptoethanol. Add lOul of inhibitor in 0.1% DMSO. Add lOul of
Mg ATP mix (50mM Mg acetate, 150uM ATP,lu€i y 33 P ATP. Incubate at room
temperature for 90 minutes. Stop the reaction by adding 50ul 20% phosphoric acid. Capture
onto P81 phosphocellulose paper (Whatman), wash in 0.5% phosphoric acid three times, dry

30 and count by liquid scintillation.

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Method 2

Mix 0.02 units of raf to 0.65u£ GST-MEK and 2.6ug GST-MAP kinase in 30u.l final
volume of buffer containing 50mM Tris-HCl pH7.4, O.lmM EGTA, lmg/ml BSA, ImM
sodium vanadate, 0.03% Brij-35, 0.1% p-mercaptoethanol. Add lOjj.1 of inhibitor in 0.1%
5 DMSO. Add lOul of Mg ATP mix (50mM Mg acetate, 1 .25mM). Incubate for 60 minutes at
room temperature. Transfer 4ul to 50ul of the same buffer containing 17ug myelin basic
protein and add lOjul of 50mM Mg acetate, 150uM ATP,luCi y 33 P ATP. Incubate at room
temperature for 10 minutes. Stop the reaction by adding 50ul 20% phosphoric acid. Capture
onto P81 phosphocellulose paper (Whatman), wash in 0.5% phosphoric acid three times, dry
1 0 and count by liquid scintillation.

The invention will now be illustrated in the following non-limiting Examples in
which, unless otherwise stated:-

(i) evaporations were carried out by rotary evaporation in vacuo and work-up
procedures were carried out after removal of residual solids by filtration;
15 (ii) operations were carried out at ambient temperature, that is in the range

18-25°C and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressure
liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or
Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck,

20 Darmstadt, Germany or high pressure liquid chromatography (HPLC) CI 8 reverse phase
silica separation;

(iv) yields are given for illustration only and are not necessarily the maximum

attainable;

(v) the end-products of the Formula (1) have satisfactory microanalyses and their
25 structures were confirmed by nuclear magnetic resonance (NMR) and mass spectral

techniques; chemical shift values were measured on the delta scale; the following
abbreviations have been used: s, singlet; d, doublet; t or tr, triplet; m, multiplet; br, broad;

(vi) intermediates were not generally fully characterised and purity was assessed by
thin layer chromatographic, HPLC, infra-red (IR) or NMR analysis;
30 (vii) melting points are uncorrected and were determined using a Mettler SP62

automatic melting point apparatus or an oil-bath apparatus; melting points for the

WO 98/22103 PCT/GB97/03102

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end-products of the Formula (1) were determined after crystallisation from a conventional
organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture;
and

(viii) the following abbreviations have been used:-

5

DMF dimethylformamide

HPLC high pressure liquid chromatography

MPLC medium pressure liquid chromatography

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PCT/GB97/03102

Example 1

N-f5-(2-Bicvclo[2.2.11hept-2-vlacetvlamino)-2-methvlphenyll-4-hvdroxvbenzamide

A solution of N-(5-amino-2-memylphenyl)-4-hydroxybenzamide
5 (133 mg) in dry DMF (0.5 ml) was added to 2-norbornanylacetic acid (77 mg) followed by a

solution of l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (96 mg) in dry

dichloromethane (3.0 ml). The reaction was stirred at ambient temperature for 5 hours. The

solvents were removed by evaporation and the residue taken up into ethyl acetate (4.0 ml) and

washed with water (3.0 ml). The aqueous layer was back extracted with ethyl acetate (4.0 ml)
10 and the combined ethyl acetate extracts were evaporated to give 95 mg (53%) of the title

product , shown to be 96% pure by HPLC using the following HPLC System:

Column HYPERS YL ODS 5\i; Flow Rate 1.5 ml/min

Dectector Wavelength 280A,; Oven Temperature 40 0C

Solvent A 1 mmol Et,N / H 2 0; Solvent B 1 mmol Et 3 N / CFLCN
15 Time 0-3 min 95%A:5%B

3-17 min gradient to 5%A:95%B

Retention Time 9.58 min.

The starting material was prepared as follows:

20 A) Oxalyl chloride (0.5 ml) was added slowly to a stirred suspension of 4-acetoxybenzoic
acid (1 .09 g), dry dichloromethane (30 ml) and DMF (one drop). The mixture is stirred for
two hours at ambient temperature. A solution of 2-methyl-5-nitroaniline (760 mg) and
pyridine (2.0 ml) in dry dichloromethane was added over 15 minutes. The reaction mixture
was stirred for a further 2 hours, washed with 5% aqueous acetic acid (2 x 25 ml), water (20

25 ml) and 5% aqueous sodium hydrogen carbonate solution. The organic extract was dried over
magnesium sulphate, filtered and evaporated to dryness. The residue was crystallised from
ethyl acetate (100 ml) to give 800 mgs (53%) of 4-acetoxy-N-(2-methyl-5-
nitrophenyl)benzamide: melting point 207-208°C.
Microanalysis: % Theory C 61.1, H 4.49, N 8.91

30 % Found C 61.0, H 4.3, N 8.8%.

NMR (DMSOd 6 ) 2.3 (3H,s); 7.31 (2H,d), 7.56 (lH,d), 8.02 (3H,m); 8.47 (lH,d), 10.12 (lH,s)

WO 98/22103 PCT/GB97/03102

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MH + = 315

B) A stirred mixture of 4-acetoxy-N-(2-methyl-5-nitrophenyl)benzamide (500 mg),
ammonium formate (1.0 g) and 10% palladium on carbon (25 mg) in methanol (10 ml) was
heated at 60°C for 2 hours. The reaction mixture was cooled and filtered through
5 diatomaceous earth (Celite®). The filtrate was evaporated to dryness and the residue
triturated with water. The crude product was filtered from the aqueous solution and
crystallised from methanol to give 140 mg (31% yield) of N-(5-amino-2-methyIphenyl)-4-
hydroxybenzamide .
Melting point 277-278°C.
10 Microanalysis: C 14 H, 4 N 2 0 2 requires C 69.4, H 5.8, N 1 1.6%; found C 69.1, H 5.8, N 1 1.5%.
NMR (DMSOd 6 ) 2.03(3H,s); 4.85(2H,s); 6.39(lH,dd); 6.61(lH,d); 6.85(3H,m); 7.82 (2H,d);
9.3(lH,s); 9.96 (lH,s)
MH + = 243

15 Example 2

N-{5-f2-(3,4-Dic hlorophenvl)acetylaminol-2-methvlDhenvl}-4-hvdroxvbenzamide

The method of Example 1 was repeated using 3,4-dichlorophenylacetic acid (0.5
mmoles). The reaction mixture was evaporated and the residue taken up in ethyl acetate (4
ml), washed with 1M hydrochloric acid (3.0 ml) and water (3.0 ml). The ethyl acetate extract
20 was evaporated to give the desired product, 132mg (68%), shown to be 92% pure by HPLC.
NMR (DMSO-d 6 ) 5: 2.23 (s, 3H), 3.73 (s, 2H), 6.93 (d, 2H) 7.23 (d, 1H), 7.35-7.46 (m, 2H),
7.60-7.70 (m, 3H), 7.92 (d, 2H), 9.60 (s, 1H), 10.08 (s, 1H), 10.19 (s, 1H).

Example 3

25 N-f5-(3-Dimethvlaminobenzamido)-2-methvlDhenvn-4-hydroxvbenzamide

N-(5-Amino-2-methylphenyl)-4-hydroxybenzamide (85 mg) was added to a stirred
solution of 3-dimethylaminobenzoic acid (89 mg) in dry DMF (0.5 ml) followed by a solution
of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (103 mg) in dry
dichloromethane (3 ml) and 4-dimethylaminopyridine (131 mg). The reaction was stirred at
30 ambient temperature under argon for 18 hours. The reaction mixture was purified by MPLC

WO 98/22103 PCT/GB97/03102

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on silica eluting in turn with 50%, 60% and 70% ethyl acetate in isohexane to give 17 mg
(11%) of the title product.

Microanalysis: % Theory C 68.6, H 5.8, N 10.3 (0.2 CH 2 C1 2 )
% Found C 68.1, H 5.7, N 10.9
5 NMR data (DMSO d 6 ) S 2.17 (s, 3H); 2.96 (s, 6H); 6.80 - 6.95(m, 3H); 7.15 - 7.35 (m, 4H);
7.58 (dd, 1H); 7.79 (d, 1H); 7.87 (d, 2H); 9.62 (s, 1H), 9.95(s, lH),10.10(s, 1H),
MFf = 390.

Example 4
10 Pharmaceutical compositions:

The following illustrate representative pharmaceutical dosage forms of the invention
as defined herein (the active ingredient being termed "Compound X"), for therapeutic or
prophylactic use in humans:

15 (a) Tablet I mg/tablet

Compound X 100

Lactose Ph. Eur 182.75

Croscarmellose sodium 12.0

Maize starch paste (5% w/v paste) 2.25

20 Magnesium stearate 3.0

(b) Tablet II mg/tablet

Compound X 50

Lactose Ph.Eur 223.75

25 Croscarmellose sodium 6.0

Maize starch 15.0

Polyvinylpyrrolidone (5% w/v paste) 2.25

Magnesium stearate 3.0

30

WO 98/22103 PCT/GB97/03102

-25 -

(c) Tablet III mg/tablet

Compound X 1.0

Lactose Ph. Eur 93.25

Croscarmellose sodium 4.0

Maize starch paste (5% w/v paste) 0.75

Magnesium stearate 1 .0

(d) Capsule mg/capsule

Compound X 10

10 Lactose Ph.Eur 488.5

Magnesium 1.5

(e) Injection I (50 mg/ml)
Compound X 5.0% w/v

15 1 M Sodium hydroxide solution 15 .0% v/v

0.1M Hydrochloric acid
(to adjust pH to 7.6)

Polyethylene glycol 400 4.5% w/v

Water for injection to 100%

20

(f) Inj ection II (10 mg/ml)

Compound X 1.0% w/v

Sodium phosphate BP 3.6% w/v

0.1M Sodium hydroxide solution 15.0% v/v

25 Water for injection to 100%

30

WO 98/22103

-26-

(g) Injection III (lmg/ml, buffered to pH6)

Compound X 0.1% w/v

Sodium phosphate BP 2.26% w/v

Citric acid 0.38% w/v

Polyethylene glycol 400 3.5% w/v

Water for injection to 100%

PCT/GB97/03102

(h) Aerosol I mg/ml
Compound X 10.0

10 Sorbitan trioleate 13 5

Trichlorofluoromethane 910.0

Dichlorodifluoromethane 490.0

(i) Aerosol II mg/ml
15 Compound X 0.2

Sorbitan trioleate 0.27

Trichlorofluoromethane 70.0

Dichlorodifluoromethane 280.0

Dichlorotetrafluoroethane 1 094.0

20

(j) Aerosol III mg/ml

Compound X 2.5

Sorbitan trioleate 3.38

Trichlorofluoromethane 67.5

25 Dichlorodifluoromethane 1086.0

Dichlorotetrafluoroethane 191.6

30

WO 98/22103 PCT/GB97/03102

-27-

(k) Aerosol IV mg/ml

Compound X 2.5

Soya lecithin 2.7

Trichlorofluoromethane 67.5

Dichlorodifluoromethane 1086.0

Dichlorotetrafluoroethane 191.6

(1) Ointment m l

Compound X 40 mg

10 Ethanol 300 pi

Water 300 pi

1 -Dodecylazacycloheptan-2-one 50 pi

Propylene glycol to 1 ml

15 Note

The above formulations may be obtained by conventional procedures well known in
the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for
example to provide a coating of cellulose acetate phthalate. The aerosol formulations (h)-(k)
may be used in conjunction with standard, metered dose aerosol dispensers, and the
20 suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative
suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80,
polyglycerol oleate or oleic acid.

WO 98/22103

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PCT/GB97/03102

Claims

1 . A pharmaceutical composition comprising an inhibitor of raf kinase of the formula I

R 3

,(R 2 ) P

Formula I

5 wherein:

R 1 and R 2 , which may be the same or different are selected from
hydroxy, C,_ 6 alkoxy, mercapto, C,_ 6 alkylthio, amino, C,. 6 alkylamino,
di-(C,. 6 alkyl)amino, carboxy, C,_ 6 alkoxycarbonyl, carbamoyl, C,. 6 alkylcarbamoyl,
di-C,. 6 alkylcarbamoyl, C,. 6 alkylsulphonyl, arylsulphonyl, C,. 6 alkylaminosulphonyl,
10 di-(C,. 6 alkyl)aminosulphonyl, nitro, cyano, cyanoC,. 6 alkyl, hydroxyC,. 6 alkyl, aminoC,. fi alkyl,
C,_ 6 alkanoylamino, C,. 6 alkoxycarbonylamino, C,. 6 alkanoyl, C,. 6 aIkanoyloxy, C,. 6 alkyl, halo,
trifluoromethyl, aryl, arylC,. 6 alkyl, arylC,. 6 alkoxy, heteroaryl, heteroarylC,„ 6 alkyl,
heterocyclyl and heterocyclylC,. 6 alkyl;

p, which may take the same or different values for R 1 and R 2 , is 0-3, and when p is 2 or 3 each
1 5 group may be the same or different;
R 3 is C M alkyl;
q is 0-4;

R 4 is aryl or cycloalkyl wherein R 4 is optionally substituted with upto 3 substituents having
any value defined for R 1 ;

20 or a pharmaceutical^ acceptable salt or in vivo hydrolysable ester thereof and a
pharmaceutical^ acceptable carrier with the proviso that N-[5-(3-cyclohexyl-
propionylamino)-2-methylphenyl]-4-hydroxybenzamide,_N-[5-(3-
cyclopentylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
phenylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(4-

25 cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(2-
cyclohexylacetylamino)-2-methy lphenyl] -4-acetoxybenzamide, N- [5 -(3 -
cyclohexylpropionylamino)-2-methylphenyl]-4-aminobenzamide, _N-[5-(3-

WO 98/22103

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PCT/GB97/03102

cyclohexylpropionylamino)-2-methylphenyl]-4-nitrobenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxymethylbenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-mcthoxycarbonylbenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-2-hydroxybenzamide, N-[5-(3-
5 cyclohexylpropionylamino)-2-methylphenyl]-3-hydroxybenzamide,

N- [5 -(3 -cyclohexy lpropiony lamino)-2-methy lphenyl]benzamide, N- [5 -(3 -
cyclohexylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide and N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxybenzamide are excluded.

10 2. A pharmaceutical composition according to claim 1 wherein R3 is methyl.

3. A pharmaceutical composition according to either claim 1 or claim 2 wherein R4 is
optionally substituted phenyl.

4. A pharmaceutical composition according to any one of claims 1 to 3 wherein p in
15 (R2)pis0.

5. A compound of the formula (I) as defined in any one of claims 1 to 4 or a
pharmaceutically-acceptable salt or in vivo hydrolysable ester thereof for use as a
medicament.

20

6. A compound of the formula (I) as defined in any one of claims 1 to 4 or a
pharmaceutically-acceptable salt or in vivo hydrolysable ester thereof for use in treating a
disease condition mediated by raf kinase.

25 7.

An inhibitor of raf kinase of formula II:

WO 98/22103

-30 -

PCT/GB97/03102

wherein:

R 1 and R 2 , which may be the same or different are selected from
hydroxy, C,_ 6 alkoxy, mercapto, C,. 6 alkylthio, amino, C,. 6 alkylamino,
5 di-(C,. 6 alkyl)amino, carboxy, C,. 6 alkoxycarbonyl, carbamoyl, C,. 6 alkylcarbamoyl,
di-C,. 6 alkyIcarbamoyl, C,. 6 alkylsulphonyl, arylsulphonyl, C,_ 6 alkylaminosulphonyl,
di-(C,. 6 alkyl)aminosulphonyl, nitro, cyano, cyanoC,. 6 alkyl, hydroxyC,. 6 alkyl, amino Chalky 1,
C,_ 6 alkanoylamino, C,. 6 alkoxycarbonylamino, C,. 6 alkanoyl, C,. 6 alkanoyloxy, C,. 6 alkyl, halo,
trifluoromethyl, aryl, arylC,. 6 alkyl, arylC,. 6 alkoxy, heteroaryl, heteroarylC N6 alkyl,
10 heterocyclyl and heterocyclylC,. 6 alkyl;

p, which may take the same or different values for R 1 and R 2 , is 0-3, and when p is 2 or 3 each
group may be the same or different;
R 3 isC,. 4 alkyl;
q is 0-4;

15 R 5 is selected from hydroxy, C,. 6 alkoxy, mercapto, C,_ 6 alkylthio, amino, C,. 6 alkylamino,
di-(C,. 6 alkyl)amino, carboxy, C,. 6 alkoxycarbonyl, carbamoyl, C,_ 6 alkylcarbamoyl,
di-C,_ 6 alkylcarbamoyl, C,. 6 alkylsulphonyl, arylsulphonyl, C,. 6 alkylaminosulphonyl,
di-(C,. 6 alkyl)aminosulphonyl, nitro, cyano, cyanoC,. 6 alkyl, hydroxyC,. 6 alkyl, aminoC l 6 alkyl,
C,. 6 alkanoylamino, C,. 6 alkoxycarbonylamino, C,. 6 alkanoyl, C ] 6 alkanoyloxy, halo, and

20 trifluoromethyl,

or a pharmaceutical^ acceptable salt or in vivo hydrolysable ester thereof with the proviso

that methyl 3-[5-(3-methoxycarbonylbenzamido)-2-methylphenylaminocarbonylbenzoate is
excluded.

8. A compound which is

25 N-[5-(2-bicyclo[2.2.1]hept-2-ylacetylamino)-2-methylphenyl]-4-hydroxybenzamide;
N- { 5-[2-(3 ,4-dichlorophenyl)acetylamino] -2-methylphenyl } -4-hydroxybenzamide;

WO 98/22103

-31 -

PCT/GB97/03102

N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-4-hydroxybenzamide; or

N-{5-[2-(3-N^-dimethylaminophenyl)acetylamino]-2-methylphenyl}-4-hydroxybenzami
or a pharmaceutically-acceptable salt or in vivo hydrolysable ester thereof.

5 9. Use of a compound of the formula (I) as defined in any one of claims 1 to 4 or N-[5-
(3-cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxybenzamide,JN-[5-(3-
cyclopentylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
phenylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(4-
cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(2-

1 0 cyclohexylacetylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-aminobenzamide, _N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-nitrobenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxymethylbenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-methoxycarbonylbenzamide, N-[5-(3-

1 5 cyclohexylpropionylamino)-2-methylphenyl]-2-hydroxybenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-3-hydroxybenzamide,
N-[5-(3-cyclohexylpropionylamino)-2-methylphenyl]benzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide or N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxybenzamide

20 or a pharmaceutically-acceptable salt thereof or an in vivo hydrolysable ester thereof in the
preparation of a medicament for treating a disease or medical condition mediated by raf
kinase.

10. Use of a compound of the formula (I) as defined in any one of claims 1 to 4 or N-[5-
25 (3 -cyclohexylpropiony lamino)-2-methylphenyl]-4-hydroxybenzamide, N- [5 -(3 -
cyclopentylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
phenylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(4-
cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(2-
cyclohexylacetylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
3 0 cyclohexylpropiony lamino)-2 -methy lpheny 1] -4-aminobenzamide, _N- [5 -(3 -
cyclohexylpropionylamino)-2-methylphenyl]-4-nitrobenzamide, N-[5-(3-

WO 98/22103

-32 -

PCT/GB97/03102

cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxymethylbenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-methoxycarbonylbenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-2-hydroxybenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-3-hydroxybenzamide,
5 N- [5 -(3 -cyclohexy lpropionylamino)-2-methy lpheny l]benzamide, N- [5 -(3 -
cyclohexylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide or N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxybenzamide or a pharmaceutically-
acceptable salt thereof or an in vivo hydrolysable ester thereof in the preparation of a
medicament for treating cancer.

10

11. A method of treating a disease or medical condition mediated by raf kinase comprising
administering to a warm-blooded animal an effective amount of a compound of the formula
(I) as defined in any one of claims 1 to 4 or N-[5-(3-cyclohexylpropionylamino)-2-
methylphenyl]-4-hydroxybenzamide, N-[5-(3-cyclopentylpropionylamino)-2-methylphenyl]-

1 5 4-acetoxybenzamide, N-[5-(3-phenylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide,
N-[5-(4-cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(2-
cyclohexylacetylamino)-2-methylphenyl] -4-acetoxybenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-aminobenzamide, _N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-nitrobenzamide, N-[5-(3-

20 cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxymethylbenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-methoxycarbonylbenzamide, N-[5-(3-
cyclohexy lpropiony lamino)-2-methylphenyl] -2-hydroxybenzamide, N- [5 -(3 -
cyclohexylpropionylamino)-2-methylphenyl]-3-hydroxybenzamide,
N-[5-(3-cyclohexylpropionylamino)-2-methylphenyl]benzamide, N-[5-(3-

25 cyclohexylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide or N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxybenzamide,
or a pharmaceutically-acceptable salt thereof.

12. A method of providing a raf kinase inhibitory effect comprising administering to a warm-
30 blooded animal an effective amount of a compound of the formula (I) as defined in any one of

claims 1 to 4 or N-[5-(3-cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxybenzamide,

WO 98/22103

-33 -

PCT/GB97/03102

N-[5-C3-cyclopentylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide. N-[5-(3-
phenylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(4-
cyclohexylbutyrylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(2-
cyclohexylacetylamino)-2-methylphenyl]-4-acetoxybenzamide, N-[5-(3-
5 cyclohexylpropionylamino)-2-methylphenyl]-4-aminobenzamide, _N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-nitrobenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxymethylbenzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-methoxycarbonylbenzamide ? N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-2-hydroxybenzamide, N-[5-(3-
10 cyclohexylpropionylamino)-2-methylphenyl]-3-hydroxybenzamide,

N-[5-(3-cyclohexylpropionylamino)-2-methylphenyl]benzamide, N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-acetoxybenzamide or N-[5-(3-
cyclohexylpropionylamino)-2-methylphenyl]-4-hydroxybenzamide,
or a pharmaceutically-acceptable salt thereof.

13. A process for preparing a compound of the formula I or a pharmaccutically acceptable
salt or in vivo hydrolysable ester thereof which process comprises:
reacting a compound of the Formula III:

15

N-H

Formula III

/

20

H

with a compound of the Formula IV

O

(CH 2 ) q

Formula IV

WO 98/22103 PCT/GB97/03102

-34-

or an activated derivative thereof , under standard amide bond forming conditions, wherein
variable groups are as hereinbefore defined wherein any functional group is protected, if
necessary, and:

i. removing any protecting groups;

ii. optionally forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.

Interi.-nonal Application No

PCT/GB 97/03102

A. CLASSIFICATION OF SUBJECT MATTER

IPC 6 A61K31/165 C07C235/56

According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)

IPC 6 A61K CG7C

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practical, search terms used)

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category °

Citation of document, with indication, where appropriate, of the relevant passages

Relevant to claim No.

A

WO 93 04170 A (US GOVERNMENT) 4 March 1993

11,12

see the whole document

A

ASHTON ET AL. : "New Low-Density

13

Lipoprotein Receptor Upregul ators Acting

via a Novel Mechanism"

0. MED. CHEM. ,

vol. 39, 1996,

pages 3343-3356, XP002054111

cited in the application

see pages 3344-3345, schemes la-4a

□

Further documents are listed in the continuation of box C.

Patent family members are listed in annex.

0 Special categories of cited documents :

"A" document defining the general state of the art which is not

considered to be of particular relevance
"E" earlier document but published on or after the international

filing date

"L" document which may throw doubts on priority claim(s) or
which is cited to establish the publication date of another
citation or other special reason (as specified)

"O" document referring to an oral disclosure, use, exhibition or
other means

"P" document published prior to the international filing date but
later than the priority date claimed

"T" later document published after the international filing date
or priority date and not in conflict with the application but
cited to understand the principle or theory underlying the
invention

"X" document of particular relevance; the claimed invention
cannot be considered novel or oannot be considered to
involve an inventive step when the document is taken alone

"Y" document of particular relevance; the claimed invention

cannot be considered to involve an inventive step when the
document is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
in the art.

"&" document member of the same patent family

Date of the actual completion of the international search

2 February 1998

Date of mailing of the international search report

13. 02. 98

Name and mailing address of the ISA

European Patent Office, P.B. 5818 Patentlaan 2
NL - 2280 HV Rijswijk

Tel. (+31-70) 340-2040, Tx. 31 651 epo nl,
Fax: (+31-70) 340-3016

Authorized officer

Engl , B

!=erm FCT. I3- '210 (second sneet; (July 19&>i

INTERNATIONAL SEARCH REPORT

Information on patent family members

Inten. atonal Application No

PCT/GB 97/03102

Patent document
cited in search report

Publication
date

Patent family
member(s)

Publication
date

WO 9304170 A

04-03-93

AU 2552492 A

16-03-93

Form PCT'I3A,210 (patent family annex) (July \S22)